Catalytic C—H amination has proven to be a successful strategy to prepare new C—H bonds without the need for a pre-functionalized site. As compared to more traditional means of C—N bond formation involving functional group manipulations (e.g., “hydroxyl to amine”), C—H amination offers the promise to cut out synthetic steps and potentially decrease the amount of by-products formed to affect a new C—N bond. Several catalytic protocols based on Rh, Ru, Ag, Cu, and other metals for amination of benzylic or allylic C—H bonds with iminoiodanes bearing electron-deficient N-substituents represent a useful methodology for the transformation of C—H to C—N bonds. C. Liang, F. Collet, F. Robert-Peillard, P. Muller, R. H. Dodd, P. Dauban, J. Am. Chem. Soc. 2008, 130, 343; K. W. Fiori, J. Du Bois, J. Am. Chem. Soc. 2007, 129, 562; R. P. Reddy, H. M. L. Davies, Org. Lett. 2006, 8, 5013; J.-L. Liang, S.-X. Yuan, J.-S. Huang, W.-Y. Yu, C.-M. Che, Angew. Chem. Int. Ed. 2002, 41, 3465; X.-Q. Yu, J.-S. Huang, X.-G. Zhou, C.-M. Che, Org. Lett. 2000, 2, 2233; Z. Li, D. A. Capretto, Rahaman, C. He, Angew. Chem. Int. Ed. 2007, 46, 5184; Y. Cui, C. He, Angew. Chem. Int. Ed. 2004, 43, 4210; M. R. Fructos, S. Trofimenko, M. M. Días-Requejo, P. J. Pérez, J. Am. Chem. Soc. 2006, 128, 11784; M. M. Díaz-Requejo, T. R. Belderraín, M. C. Nicasio, S. Trofimenko, P. J. Pérez, J. Am. Chem. Soc. 2003, 125, 12078; H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417; P. Dauban, R. H. Dodd, in Amino Group Chemistry (Ed.: A. Ricci), Wiley-VCH, Weinheim, 2008, pp. 55; and P. Müller, C. Fruit, Chem. Rev. 2003, 103, 2905. Studies by Du Bois and other have shown its compatibility in the synthesis of more elaborate product. Importantly, retention of stereochemistry is commonly observed in these transformations.
A disadvantage of this promising methodology is that highly functionalized, electron-deficient nitrene precursors such as sulfonylamines must be used in conjunction with expensive and environmentally unfriendly oxidants, such as PhI(OAc)2. See FIG. 1A. The resulting amines must be deprotected to give the more synthetically useful primary amines. Moreover, expensive rhodium based catalysts Rh2L4 are typically used in 2-5 mol % in the most successful systems.
In addition to iminoiodane nitrene precursors PhI═NSO2R (M. R. Fructos, S. Trofimenko, M. M. Días-Requejo, P. J. Pérez, J. Am. Chem. Soc. 2006, 128, 11784; M. M. Díaz-Requejo, T. R. Belderraín, M. C. Nicasio, S. Trofimenko, P. J. Pérez, J. Am. Chem. Soc. 2003, 125, 12078), some copper systems allow for the amination of benzylic and allylic C—H bonds employing activated secondary amines such as MeNHSO2Ph and t-butylperacetate. Use of 5 mol % copper(II) triflate and 1,10-phenanthroline as catalyst results in good yields for benzyling and allylic amination of a number of substrates (G. Pelletier D. A. Powell, Org. Lett 2006, 8, 6031.) The use of secondary amines suggests that some mechanism that does not involve metal-nitrene intermediates [Cu]═NR is likely operative, as shown below.
Nonetheless, a strong electron-withdrawing group such as sulfonyl on the secondary amine is required to enable this C—H amination reaction. This sulfonyl group would generally be deprotected in a in further synthetic elaboration of the C—H amination product, detracting from the atom economy of this transformation.
Recently, a new copper-based catalyst system for C—H amination with organoazides was disclosed. See FIG. 1B. Copper is a particularly attractive metal for catalysis, approximately 10,000-25,000 times less expensive than rhodium. Using an inexpensive, easy-to-prepare β-diketiminate supporting ligand, dicopper nitrenes [Cu]2(μ-NR) have been identified as meta-stable isolable intermediates in C—H amination reactions. T. H. Warren (Georgetown University), PCT Int. Appl. WO 2008073781, 2008; and Y. M. Badiei, A. Krishnaswamy, M. M. Melzer, T. H. Warren, J. Am. Chem. Soc. 2006, 128, 15056. These species, initially prepared by organozides, can be isolated, crystallized, spectroscopically characterized. Presumably via a dissociation reaction to give a terminal nitrene [Cu]═NR and [Cu], they participate in C—H amination reactions. Dissolution of {[Cl2NN]Cu}2(μ-NAd) in toluene, indane, or cyclohexane at room temperature or with heating to 80° C. resulted in adamantylnitrene transfer to give the corresponding amination products.
Importantly, this valuable C—H functionalization reaction is amendable to catalytic protocols. Heating a number of neat substrates with N3Ad in the presence of 2.5 mol % {[Cl2NN]Cu}2(benzene) gives rise to high amination yields. See FIG. 2. The use of only one equivalent of substrate in benzene solvent also leads to 80+% yields for secondary benzylic substrates such as ethylbenzene and indane as well as amidation of benzaldehyde in 91% yield. The rate of C—H amination is strongly correlated with strength of the reacting C—H bond, allowing means for selectivity.
The amination of aldehydes has also been reported. However, these reactions are limited to the use of primary organic amines (H2NR), their hydrochloride salts (see W.-J. Yoo, C.-J. Li J. Am. Chem. Soc. 2006, 128, 13064, as discussed below), or primary sulfonylamines (H2NSO2R; see J. Chan, K. D. Baucom, J. A. Murry J. Am. Chem. Soc. 2007, 129, 14106-14107). For example, in the report by Yoo and Li (W.-J. Yoo, C.-J. Li J. Am. Chem. Soc. 2006, 128, 13064), simple copper salts are used in conjunction with AgIO3 as co-catalyst along with t-butyl hydroperoxide or T-HYDRO (69-70% tBuOOH in water) as oxidant, as shown below with a proposed mechanism:

In addition, Fu has reported the use of copper catalysts for the amidation of C—H bonds. N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS) were used as oxidants coupled with primary amides such as benzamide (H2NC(O)Ph) and tosylamine (H2NSO2(p-MeC6H4)) (see Liu, X.; Zhang, Y.; Wang, L.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73, 6207-6212; Wang, Z.; Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2008, 10, 1863-1866; and Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9, 3813-3816). For instance, a benzylic C—H bond in ethylbenzene is amidated with these two reagents using NBS and CuBr (20 mol %) in 50 and 65% yield. FeCl2 at 10 mol % catalyst loadings also serves as an inexpensive catalyst for similar reactions with NBS.

Both primary and secondary amides could be employed in the amidation of N,N-dimethylaniline derivates using NCS and tBuOOH as oxidants under CuBr catalysis (20 mol % and 5 mol %, respectively).

However, there remains a need for amination methods which avoid the need for more highly functionalized precursors, such as alcohols, aldehydes, ketones as well as organoazides. In addition, there remains a need for a method of amination of aldehydes which is not limited to primary amines, and their hydrochoride salts, and primary sulfonamides. Further, an amination method for unactivated substrates, and one which uses an easy-to-remove oxidant, is also desirable.